DESCRIPTION (Scanned from the applicant's description): Cigarette smoking is associated with a higher risk for chronic diseases, such as heart disease and cancer; oxidative damage is one of the contributing causes of these increased risks. Free radical products from cigarette smoking and from activated neutrophils contribute to the observed oxidative damage. Vitamin E is the most potent, lipid soluble antioxidant in plasma, and exposure of human plasma to smoke in vitro results in depletion of vitamin E. Smokers' plasma contains low ascorbic acid levels, low to normal vitamin B levels and increased lipid peroxidation products. However, to date, there is no direct evidence in humans that vitamin E prevents oxidative damage. Our specific goal is to evaluate whether antioxidant supplementation might ameliorate some of the oxidative damage that results from cigarette smoking. We propose the following: 1) Cigarette smoking increases oxidative damage and thus, increases vitamin B turnover. 2) In subjects taking vitamin C supplements, increased vitamin C levels decrease oxidative damage and reduce vitamin E radicals, thus protecting vitamin E and decreasing vitamin B turnover. 3) Oxidation products resulting from cigarette smoking induce a protective mechanism that causes more vitamin E to be secreted from the liver into the plasma. These hypotheses will be addressed in three trials. In Trial 1, vitamin B kinetics will be measured in smokers and non-smokers using vitamin B labeled with stable isotopes to determine whether smokers have increased vitamin B fractional catabolic rates (FCRs). In Trial 2, the same group of subjects (after a washout period) will be given vitamin C supplements, 500 mg twice a day for 1 month prior to and then during the vitamin B kinetics study. We will assess whether vitamin C supplements decrease vitamin E FCRs. In Trial 3, three different forms of vitamin E, labeled with differing amounts of deuterium, will be administered to assess whether hepatic secretion of the only regulated form of vitamin B (RRR-a-tocopherol) is increased in response to the oxidative stress of smoking. Markers of lipid peroxidation (plasma lipid hydroperoxides and F2-isoprostanes) and plasma ascorbic acid will be measured throughout all three trials to document levels of oxidative damage. These proposed studies will further our goal of understanding the role of vitamin E in the amelioration of oxidative damage in aging and in chronic diseases, such as heart disease, diabetes and cancer.